Solute carriers keep on rockin'

Reithmeier, Reinhart A.F.; Moraes, Trevor F.

doi:10.1038/nsmb.3104

Cited by 9 publications

(4 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The overall folds of UraA (Uracil Transporter, E. coli) (Lu et al, 2011), SLC26Dg (SLC26, Deinococcus geothermalis) (Geertsma et al, 2015) and the Band 3 (SLC4A1) (Arakawa et al, 2015) structures are similar in containing "7 þ 7" inverted TMs repeats which constitute the "core" and "gate" domain. Specifically, all these structures share a unique "beta strand followed by short alpha helix" (Reithmeier & Moraes, 2015) in the crossed TM 3 and its symmetry-related TM 10. The N-termini of these two short helices faces each other in the center of the protein providing a binding site for anionic substrates between the positive helix dipoles (Reithmeier et al, 2016).…”

Section: Disease Relationshipmentioning

confidence: 99%

“…The N-termini of these two short helices faces each other in the center of the protein providing a binding site for anionic substrates between the positive helix dipoles (Reithmeier et al, 2016). A proton-binding site in Band 3 (SLC4A1) that is required for sulfate uptake is identified at Glu681, while the equivalent Glu241 in SLC26Dg is proposed to be the proton-binding site (Reithmeier & Moraes, 2015) but this needs verification (Geertsma et al, 2015). However, the corresponding residues are not conserved in human SLC26s since SLC26s in human operate as exchangers, rather than as proton (or sodium)-driven co-transporters.…”

Section: Disease Relationshipmentioning

confidence: 99%

“…However, the corresponding residues are not conserved in human SLC26s since SLC26s in human operate as exchangers, rather than as proton (or sodium)-driven co-transporters. Reithmeier & Moraes (2015) further discussed that in sodium-driven bicarbonate cotransporters (NBCs), that Glu681 has been replaced by Asp compared with proton-driven transporters, due to a changing in the driving force. In addition, the smaller Asp can likely accommodate the larger sodium ion than the Glu required for proton binding.…”

Section: Disease Relationshipmentioning

confidence: 99%

See 2 more Smart Citations

Structural biology of solute carrier (SLC) membrane transport proteins

Bai

Moraes

Reithmeier

2017

Molecular Membrane Biology

142

101

View full text Add to dashboard Cite

The human solute carriers (SLCs) comprise over 400 different transporters, organized into 65 families (http://slc.bioparadigms.org/) based on their sequence homology and transport function. SLCs are responsible for transporting extraordinarily diverse solutes across biological membranes, including inorganic ions, amino acids, lipids, sugars, neurotransmitters and drugs. Most of these membrane proteins function as coupled symporters (co-transporters) utilizing downhill ion (H þ or Na þ) gradients as the driving force for the transport of substrate against its concentration gradient into cells. Other members work as antiporters (exchangers) that typically contain a single substrate-binding site with an alternating access mode of transport, while a few members exhibit channel-like properties. Dysfunction of SLCs is correlated with numerous human diseases and therefore they are potential therapeutic drug targets. In this review, we identified all of the SLC crystal structures that have been determined, most of which are from prokaryotic species. We further sorted all the SLC structures into four main groups with different protein folds and further discuss the well-characterized MFS (major facilitator superfamily) and LeuT (leucine transporter) folds. This review provides a systematic analysis of the structure, molecular basis of substrate recognition and mechanism of action in different SLC family members.

show abstract

Section: Disease Relationshipmentioning

confidence: 99%

Section: Disease Relationshipmentioning

confidence: 99%

Section: Disease Relationshipmentioning

confidence: 99%

See 1 more Smart Citation

Structural biology of solute carrier (SLC) membrane transport proteins

Bai

Moraes

Reithmeier

2017

Molecular Membrane Biology

142

101

View full text Add to dashboard Cite

show abstract

“…SLC4A11 is the only SLC4 family member without an arginine at this position, and is also the only SLC4 member with no HCO 3 − transport activity [Reithmeier et al., ]. Conserved through all SLC4 family members is a glutamate within the catalytic pore, Glu675 in SLC4A11, which is proposed to act as a gate, occupying the anion binding site when no substrate is present [Reithmeier and Moraes, ; Reithmeier et al., ].…”

Section: Discussionmentioning

confidence: 99%

SLC4A11 Three-Dimensional Homology Model Rationalizes Corneal Dystrophy-Causing Mutations

2016

View full text Add to dashboard Cite

We studied the structural effects of point mutations of a membrane protein that cause genetic disease. SLC4A11 is a membrane transport protein (OH /H /NH /H O) of basolateral corneal endothelium, whose mutations cause some cases of congenital hereditary endothelial dystrophy and Fuchs endothelial corneal dystrophy. We created a three-dimensional homology model of SLC4A11 membrane domain, using Band 3 (SLC4A1) crystal structure as template. The homology model was assessed in silico and by analysis of mutants designed on the basis of the model. Catalytic pathway mutants p.Glu675Gln, p.His724Arg, and p.His724Ala impaired SLC4A11 transport. p.Ala720Leu, in a region of extended structure of the proposed translocation pore, failed to mature to the cell surface. p.Gly509Lys, located in an open region at the core domain/gate domain interface, had wild-type level of transport function. The molecular phenotype of 37 corneal dystrophy-causing point mutants was rationalized, based on their location in the homology model. Four map to the substrate translocation pathway, 25 to regions of close transmembrane helix packing, three to the dimeric interface, and five lie in extramembraneous loops. The model provides a view of the spectrum of effects of disease mutations on membrane protein structure and provides a tool to analyze pathogenicity of additional newly discovered SLC4A11 mutants.

show abstract

Structural Changes Fundamental to Gating of the Cystic Fibrosis Transmembrane Conductance Regulator Anion Channel Pore

Linsdell

2016

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial cell anion channel. Potentiator drugs used in the treatment of cystic fibrosis act on the channel to increase overall channel function, by increasing the stability of its open state and/or decreasing the stability of its closed state. The structure of the channel in either the open state or the closed state is not currently known. However, changes in the conformation of the protein as it transitions between these two states have been studied using functional investigation and molecular modeling techniques. This review summarizes our current understanding of the architecture of the transmembrane channel pore that controls the movement of chloride and other small anions, both in the open state and in the closed state. Evidence for different kinds of changes in the conformation of the pore as it transitions between open and closed states is described, as well as the mechanisms by which these conformational changes might be controlled to regulate normal channel gating. The ways that key conformational changes might be targeted by small compounds to influence overall CFTR activity are also discussed. Understanding the changes in pore structure that might be manipulated by such small compounds is key to the development of novel therapeutic strategies for the treatment of cystic fibrosis.

show abstract

Solute carriers keep on rockin'

Cited by 9 publications

References 26 publications

Structural biology of solute carrier (SLC) membrane transport proteins

Structural biology of solute carrier (SLC) membrane transport proteins

SLC4A11 Three-Dimensional Homology Model Rationalizes Corneal Dystrophy-Causing Mutations

Structural Changes Fundamental to Gating of the Cystic Fibrosis Transmembrane Conductance Regulator Anion Channel Pore

Contact Info

Product

Resources

About